Somatic mutations in mitochondrial DNA (mtDNA) have been regarded as a hallmark of cancer. However, the role of germline variations (polymorphisms) in mtDNA in cancer development is largely unknown. The mitochondrial genome is highly polymorphic among individuals and exhibits significant geographic and racial difference. It has been suggested that some mtDNA variants could have adverse effect by increase the generation of reactive oxygen species (ROS). The accumulation of those adverse effects over time may increase individual's cancer risk. Besides the sequence variations in mtDNA, the copy number of mitochondria might also affect cancer risk by disturbing crosstalk between mitochondrial and nucleus and consequently altering nuclear DNA stability. It has been proposed that the copy number of mitochondria per cell reflects the gene-environmental interactions between unknown hereditary factors and levels of oxidative stress. However, whether the copy number of mitochondria could be a predictor of human cancer development remains to be determined. Variability in MtDNA sequence and copy number of mitochondria might be extremely relevant to breast cancer because oxidative stress has been suggested to play a significant role in breast cancer etiology. Considerable efforts have been made to discover breast cancer susceptibility genes. However, few have been identified to date. The dilemma might be due to the fact that some of the susceptibility alleles might not reside in nuclear DNA, but in mtDNA. More intriguingly, the geographic and racial difference of mtDNA polymorphisms might have implications in breast cancer racial disparity because African American women are at disproportionately high risk for many oxidative stress-related medical conditions, including breast cancer. Therefore, the investigation of the role of mitochondrial as a predisposition factor of breast cancer could have significant impact. In current proposal, we plan to utilize the valuable biospecimens and data collected through an ongoing case-control study (7R01CA100598) to comprehensively investigate the associations between mtDNA polymorphisms/haplogroups and breast cancer risk in both Caucasian American (CA) and African American (AA) women. We will also examine the associations between the copy number of mitochondria and breast cancer risk. In further analysis, we will study whether mtDNA polymorphisms/haplogroups and copy number of mitochondria are associated with aggressive clinical characteristics of breast cancer. Because the proposed research is nested within an ongoing study, the objectives can be addressed in a timely and cost effective manner. The study will further our understanding of the genetic events leading to the development of breast cancer;explore the genetic basis linking mitochondrial, ROS and breast cancer;find the clues for breast cancer racial disparity, and eventually provide a means of identifying a subgroup that are most likely to develop breast cancer. Such individuals may then be targeted for specific intervention programs such as chemoprevention and dietary modification. PUBLIC HEALTH RELEVANCE: NARRATIVE Given the fact that mitochondrial produces energy and generate ROS, inherited variations in mtDNA might represent a newly described mechanism of cancer predisposition. Inherited variations in mtDNA may be extremely relevant for breast cancer, as oxidative stress has consistently been regarded as a risk factor for breast cancer. The study will further our understanding of the genetic events leading to the development of breast cancer;explore the genetic basis linking mitochondrial, ROS and breast cancer;find the clues for breast cancer racial disparity, and eventually provide a means of identifying a subgroup that are most likely to develop breast cancer. From a clinical perspective, the long-term application of this information to risk assessment and thus to the prevention and early detection of breast cancer in families as well as population will be significant.